Selenium has been the focus of considerable recent attention for its potential in reducing prostate cancer incidence. For over 25 years, selenium has been shown to be effective in preventing cancer in animal models, and human epidemiological and supplementation studies have suggested this essential trace element is effective in human as well. The mechanism of action, however, remains unknown. Selenium is a component of several dozen proteins in mammals, and recent genetic data has indicated that allelic variants of at least two selenoproteins are associated with cancer risk and/or etiology. This application is designed to study the role of selenium and selenoproteins in prostate cancer by developing a unique mouse model in which two transgenic animals are crossed: one develops prostate cancer as a result of the targeted expression of the early region of SV40 to the prostate, and the other has reduced selenoprotein levels as a result of the dominant action of a tRNA required for the synthesis of all selenium-containing proteins. These animals will be crossed to test the hypothesis that reduced selenoprotein levels will increase the incidence of pre-neoplastic lesions and tumors to the prostate, and accelerate their appearance. Animal studies will be conducted to determine whether selenium provided in the diet of these animals can influence prostate cancer development in each of the above described genetic backgrounds, as to provide mechanistic data to whether the protection provided by selenium is mediated through selenoproteins or non-selenoprotein compounds. Human prostate cells will also be used in cell culture to address the hypothesis that selenoproteins are protective by stimulating cell signaling molecules that ultimately influence DNA damage repair, and the effects of altered selenoprotein levels on these pathways in mouse prostates will be determined. Establishing a link between prostate cancer prevention, selenium and selenoprotein levels could lead to additional studies to maximize the protective effects of selenium and reduce prostate cancer incidence.